Insights into inherited genetic variations and genetic ancestry of patients with high-risk melanoma

Host genetic ancestry plays an important role in shaping somatic mutation landscapes and may influence therapeutic outcomes as well as the risk of developing treatment-related adverse events. As genetic ancestry has been associated with differential susceptibility to melanoma subtypes, distinct somatic mutation frequencies and variable responses to immune checkpoint inhibitors warrant further investigation. This study investigated the genetic ancestry of a North American melanoma population using banked biospecimens from 744 patients enrolled in the ECOG-ACRIN E1609 phase III clinical trial (stages IIIB, IIIC, M1a, or M1b). Peripheral blood samples were genotyped using the Illumina Infinium Global Screening Array v3.0 + Multi-Disease BeadChip, followed by quality control, integration with reference dataset, and linkage disequilibrium pruning (198 064 single nucleotide polymorphisms). Dimensionality reduction was performed with Uniform Manifold Approximation and Projection analysis, and genetic ancestry was inferred using unsupervised ADMIXTURE models. Most patients (728 of 744; 97.8%) had predominant European (EUR) ancestry, followed by minor representation from admixed American (12 of 744; 1.6%) and East Asian (4 of 744; 0.5%) populations. Moreover, based on ADMIXTURE model (K = 5), 96.9% of participants had an estimated EUR ancestry proportion exceeding 80%. Self-reported race and ethnicity demonstrated strong concordance with genetically inferred ancestry, although a small subset of participants exhibited discordant ancestry components. Participants who self-identified as Hispanic exhibited mixed EUR-Admixed American ancestry components. Most patients represented predominant EUR ancestry, with limited representation of non-EUR populations. Integrating ancestry-informed genomic analyses will enhance understanding of melanoma susceptibility, improve prediction of immune-related adverse events, and support the development of tailored immunotherapy strategies.